The current VA-funded research activities of the nominee fall into two major categories: studies of the chronic effects of TBI and studies of the non-motor symptoms of Parkinson's disease. With regard to TBI, current studies in the nominee's lab are focusing on the most prevalent form of TBI seen in military personnel, Veterans and civilians- repetitive, mild TBI (rmTBI). This insidious form of head injury has many comorbid psychiatric, cognitive, sleep and behavioral abnormalities associated with it yet it remains poorly understood and effective treatments for it are not available. The lab of the nominee recently developed a new animal model of rmTBI that has opened new avenues of investigation into the chronic outcomes of head injury. Initial work has established that the model can be used to deliver numerous impacts to the head of a mouse without causing skull fracture, intracranial bleeding or paralysis. However, this model is unique in that it results in many of the long-term outcomes that are being seen in Veterans and athletes to include depression- and anxiety-like affective disorders, sleep disturbances, cognitive decline and a CTE-like neuropathology. Another unique element this line of research is the testing of a new therapy for rmTBI. To date, all clinical tests of TBI therapies have failed and the possibility must be considered that the reason for this 100% failure rate is related to the use of animal models of TBI that do not faithfully create impact conditions to which humans are exposed. Our new model of rmTBI fills this gap. Soon after publication of our new model, we were approached by Acetylon Pharmaceuticals to test their new HDAC6 inhibitor as a therapy for rmTBI. Studies underway with this new compound are producing promising results and emerging tests will also determine its effectiveness in relieving the comorbid conditions that often accompany rmTBI. With regard to Parkinson's disease (PD), it is becoming that the non-motor symptoms (NMS) of this neurodegenerative disease lower the quality of life for Veterans more so than the much better understood motor symptoms. The NMS of Parkinson's can include many of the same conditions cited above for rmTBI. To date, the vast majority of preclinical and clinical studies of PD have focused on the dopamine (DA) neuronal system and how its destruction can result in disease symptomology. Most therapies for PD also target the DA system. As is the case for rmTBI, there is no effective therapy for the NMS of PD. However, while vastly underappreciated, the serotonin (5HT) and norepinephrine (NE) systems are also extensively altered in PD. The lab of the nominee has created two genetically modified mouse strains that lack brain 5HT. One is a constitutive null mutation in the gene for tryptophan hydroxylase and a new strain is a tamoxifen-inducible knockout of the same gene. The key facet that makes these mouse strains so applicable to the study of the NMS of PD is the fact that the 5HT deficits in them are very similar to those now known to occur in humans with PD- loss of function without degeneration of 5HT neurons. These 5HT deficient mice will be used to create combined monoamine deficits using neurotoxins that selectively target the DA (MPTP) and the NE (DPS-4) neuronal systems and the effects of these alterations on the emergence of NMS will be assessed. These studies will also test the natural precursors of each monoamine alone or in combination to restore function and alleviate the NMS. The overarching goal of the above described research is to improve the treatment and enhance the rehabilitation of Veterans afflicted with rmTBI and PD. This goal is extremely important because these two disorders affect a very large number of Veterans and each is frequently associated with numerous, additional comorbid disorders. Our overarching goal will be achieved by increasing the understanding of the disease mechanisms of rmTBI and PD NMS via the application of new and innovative technical approaches and through the testing of novel, rational and safe therapeutic approaches.